4 3.4. Analysis of genes differentially expressed in Lbx1 GFP/+ and Lbx1 GFP/GFP muscle precursor cells Expression of CXCR4 its ligand SDF1 in mouse and chick embryos CXCR4 is expressed in muscle precursors of hypoglossal stream, but not of the limb in Lbx1 mutant Ectopic application of SDF1 in the chick limb attracts muscle precursor cells and delays their differentiation Loss of CXCR4 affects the distribution and the number of muscle precursor cells Effect of CXCR4 mutation on the generation of skeletal muscle DISCUSSION Gene expression profiling of Lbx1 GFP/+ and Lbx1 GFP/GFP muscle precursor cells Lbx1 is not sufficient to control the expression of CXCR CXCR4 is expressed in a subpopulation of migrating muscle precursor cells CXCR4 is important for migration and survival of muscle precursor cells A genetic interaction of Gab1 and CXCR Outlook SUMMARY ZUSAMMENFASSUNG REFERENCES... 80

5 5. Summary Summary By the use of the microarray technology I have determined the gene expression profile of migrating muscle precursors of Lbx1 GFP/+ and Lbx1 GFP/GFP mutant mice. Among the expressed genes, the chemokine receptor CXCR4 was identified. Expression of CXCR4 was downregulated in Lbx1 GFP/GFP mutant mice in muscle precursors of the limb, but not in those cells that migrate to the tongue anlage. The CXCR4 ligand, SDF1, is expressed in the mesenchyme of the limb and the first branchial arch, the targets of the migrating cells. In my thesis, I analyzed the function of CXCR4 signaling in the development of migrating muscle precursors. Gain-offunction experiments of chick embryos demonstrate that SDF1 can provide attractive cues for muscle precursor cells and suppress their differentiation. Analysis of CXCR4 mutant mice demonstrates changes in the distribution of migrating muscle precursors in the dorsal limb and branchial arches. These changes were accompanied by increased apoptosis, indicating that CXCR4 signals provide not only attractive cues but control also survival. Furthermore, I found that CXCR4 and Gab1 interact genetically. Both CXCR4 and Gab1 mutations interfere with appropriate distribution and survival of migrating muscle precursor cells. However, in CXCR4;Gab1 mutant mice the migrating muscle precursors are affected more strongly than in either of the single mutants. For instance, migrating muscle precursor cells arrive at the anlage of the tongue in CXCR4 and Gab1 mutant mice, but fail to reach this site in the CXCR4;Gab1 double mutant mice. The genetic interaction of CXCR4 and Gab1 might reflect a cross-talk between signaling cascades employed by G-protein coupled receptors and tyrosine kinases.

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